Mechanisms of Resolution in Acute Vascular Injury

 描述(由申请人提供)：治疗性血管介入治疗的失败，无论是血管内的还是开放的，都是一个非常常见的临床问题，会导致显著的发病率、死亡率和成本。最后一条通向失败的共同途径是持续性炎症，导致血管壁的增殖和重塑。炎症的消退以前被认为是一个被动的过程，现在被认为是由omega-3和omega-6多不饱和脂肪酸(PUFAs)衍生的专门的促分解脂质介体(PRM)主动控制的。虽然目前的抗再狭窄药物主要通过细胞毒作用来调节细胞增殖，但最近在Conte Lab的工作表明，PRM在体外和体内都对血管平滑肌细胞(VSMC)具有细胞抑制作用。与加州大学旧金山分校的Desai实验室合作，Conte实验室还开发了一种新型的可生物降解的聚合物膜，通过它可以将RvD1可靠地输送到局部血管外膜。关于PRM调节炎症的各种机制已经研究了很多，但对PRM调控细胞增殖的具体机制知之甚少。本项目的目标是研究RvD1(一种二十二碳六烯酸衍生的D系列解析素)在体外和体内对血管平滑肌细胞的细胞抑制作用的机制，特别是它对血小板衍生生长因子(PDGF)信号通路的影响。这是非常有临床意义的 目前可用的辅助药物治疗受到其细胞毒性作用的限制，而内源性PRM可能为调节血管愈合提供一种新的治疗方法。我的第一个目标是确定RvD1对兔和人VSMC中与损伤相关的PDGF放大通路的影响。将评估VSMC的增殖、迁移和白细胞黏附。PDGF的表达将通过RNA、免疫印迹、免疫染色以及受体表达和磷酸化的测量来评估。我的第二个目标是确定局部外膜递送RvD1是否改善了兔血管成形术后的重塑，以及其机制是否涉及PDGF放大通路的减弱。使用新开发的新型可生物降解聚合物薄膜将Rvd1应用于动脉，我将评估血管成形术后早期细胞和分子事件以及动脉的晚期重塑。通过Conte实验室提供的机会和资源，我个人的目标是为我未来在翻译研究和血管生物学领域的职业发展积累有关体外和体内技术的基本知识和经验。我期待着与戴维斯博士的合作。 孔戴将激励和激励我对科学的热情，并帮助我最大限度地发挥我作为一名未来多产和创新的外科医生-科学家的潜力。

 DESCRIPTION (provided by applicant): Failure of therapeutic vascular interventions, both endovascular and open, is an exceedingly common clinical problem that incurs significant morbidity, mortality and costs. A final common pathway to failure is persistent inflammation leading to proliferation and remodeling of the vessel wall. The resolution of inflammation, formerly considered a passive process, is now understood to be actively governed by specialized pro-resolving lipid mediators (PRMs) derived from omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). While current anti-restenosis agents modulate proliferation primarily via cytotoxic effects, recent work in the Conte Lab has shown that PRMs exert cytostatic effects on vascular smooth muscle cells (VSMC) both in-vitro and in-vivo. In collaboration with the Desai Lab at UCSF, the Conte Lab has also developed a novel biodegradable polymer wrap through which RvD1 can be reliably delivered to the local vascular adventitia. Much has been studied on the various mechanisms through which PRM's modulate inflammation, however relatively little is known about the specific mechanisms through which PRM's modulate cell proliferation. The goal of my project is to characterize the mechanisms through which RvD1 (a docosahexaenoic acid-derived, or D-series, resolvin) exerts cytostatic effects on vascular smooth muscle cells, with specific attention to its effects on the platelet derived growth factor (PDGF) signaling pathway both in vitro and in vivo. This is of great clinical significance as currently available adjuvant pharmacotherapies are limited by their cytotoxicity effects, and endogenous PRMs may provide a novel therapeutic approach to regulate vascular healing. My first aim is to determine the effects of RvD1 on injury-related PDGF amplification pathways in rabbit and human VSMC. VSMC proliferation, migration, and leukocyte adhesion will be assessed. PDGF expression will be assessed via RNA, western blot, immunostaining as well as measurements of receptor expression and phosphorylation. My second aim is to determine if local adventitial delivery of RVD1 improves post-angioplasty remodeling in a rabbit model, and if the mechanism involves attenuation of PDGF amplification pathways. Using a newly-developed novel biodegradable polymer wrap to administer RvD1 to the artery, I will assess early cellular and molecular events, as well as late remodeling of arteries following angioplasty. Through the opportunities and resources provided by the Conte lab, my personal aim is to develop essential knowledge of and experience with in vitro and in vivo techniques for my future career in translational research and vascular biology. I anticipate that working with Dr. Conte will inspire and invigorate my passion for science and help me maximize my potential as a future productive and innovative surgeon-scientist.